Menon et al. BMC Infectious Diseases (2016) 16:361 DOI 10.1186/s12879-016-1718-5
REVIEW
Open Access
Convergence of a diabetes mellitus, protein energy malnutrition, and TB epidemic: the neglected elderly population Sonia Menon1,2*, Rodolfo Rossi3, Leon Nshimyumukiza4, Aibibula Wusiman5, Natasha Zdraveska6 and Manal Shams Eldin7
Abstract Background: On a global scale, nearly two billion persons are infected with Mycobacterium tuberculosis. From this vast reservoir of latent tuberculosis (TB) infection, a substantial number will develop active TB during their lifetime, with some being able to transmit TB or Multi-drug- resistant (MDR) TB to others. There is clinical evidence pointing to a higher prevalence of infectious diseases including TB among individuals with Diabetes Mellitus (DM). Furthermore, ageing and diabetes mellitus may further aggravate protein-energy malnutrition (PEM), which in turn impairs Tlymphocyte mediated immunologic defenses, thereby increasing the risk of developing active TB and compromising TB treatment. This article aims to a) highlight synergistic mechanisms associated with immunosenescence, DM and PEM in relation to the development of active TB and b) identify nutritional, clinical and epidemiological research gaps. Methods: To explore the synergistic relationship between ageing, DM, tuberculosis and PEM, a comprehensive review was undertaken. The MEDLINE and the Google Scholar databases were searched for articles published from 1990 to March 2015, using different MESH keywords in various combinations. Results: Ageing and DM act synergistically to reduce levels of interferon gamma (IFN- γ), thereby increasing susceptibility to TB, for which cell mediated immunity (CMI) plays an instrumental role. These processes can set in motion a vicious nutritional cycle which can predispose to PEM, further impairing the CMI and consequently limiting host defenses. This ultimately transforms the latent TB infection into active disease. A clinical diagnostic algorithm and clinical guidelines need to be established for this population. Conclusion: Given the increase in ageing population with DM and PEM, especially in resource-poor settings, these synergistic tripartite interactions must be examined if a burgeoning TB epidemic is to be averted. Implementation of a comprehensive, all-encompassing approach to curb transmission is clearly indicated. To this end, clinical, nutritional and epidemiological research gaps must be addressed without a delay.
Background TB infection occurs when a susceptible person inhales droplets containing Mycobacterium tuberculosis bacteria, which travel through the respiratory tract to the alveoli. In most patients, host’s immune response limits the propagation of TB infection, resulting in an asymptomatic, non-transmissible localized infection that may remain in the body for many years, if not forever. * Correspondence: [email protected] 1 International Centre for Reproductive health, Ghent University, LSHTM Alumni, Ghent, Belgium 2 CDC Foundation, Atlanta, USA Full list of author information is available at the end of the article
One in three people in the world has latent tuberculosis [1]. In 2009, approximately 9 million new cases of active TB were diagnosed and 1.7 million persons succumbed to the disease [2]. An additional challenge to TB control efforts is the global increase in multi-drug resistant TB (MDR-TB), defined as TB caused by strains resistant to at least isoniazid and rifampin. In 2013, the World Health Organization (WHO) reported that 3.6 % of the new cases and 20.2 % of the previously treated cases had MDR-TB [3]. Concurrently, diabetes mellitus (DM) is burgeoning as a worldwide chronic health condition, which can be attributed to increases in obesity, changing patterns of
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Menon et al. BMC Infectious Diseases (2016) 16:361
diet and physical activity as well as ageing [4, 5]. According to WHO estimates, there are currently 347 million people worldwide affected by DM, [6] and by 2030 its prevalence is projected to increase by 50 % [6]. 3/4 of diabetic patients live in low-income countries [7–9]. It is now well-established that cellular immune responses mediated by T cells and macrophages play a major role in the defense against TB [10]. In particular, the Th1 cytokine interferon (IFN)-γ is considered a principal mediator of protective immunity against TB [11, 12] DM is a clinical syndrome associated with deficiency of insulin secretion or resistance to its actions. Apart from the classical micro and macrovascular complications of the disease, DM has been associated with reduced T cell response and neutrophil functional activity as well as humoral immunity disorders, [13, 14] which in turn compromises the protective role that cellular immune response plays against TB. Consequently, DM patients show increased susceptibility to infections, notably TB, compared to individuals without DM [2, 15]. Some studies have shown that TB/DM comorbidity is common, both in low-income and high-income countries. [2, 16]. A 2008 systematic review of literature which identified 13 age-adjusted, quantitative, observational studies in North America, UK, Russia, Mexico, Korea, Taiwan and India reported a relative risk of TB in DM patients of 3.1 in cohort studies, with odds ratios ranging from 1.16 to 7.83 in case control studies [17]. An epidemiological model indicated that in India DM might account for nearly 15 % of pulmonary tuberculosis (PTB) cases [18]. In diabetic patients, pulmonary TB may progress rapidly and hence requires a high index of suspicion in the diagnostic phase [19]. Furthermore, the rising number of ageing diabetic population at risk for TB represents a worldwide health threat. People aged 60 and older make up over 11 % of the global population and by 2050 that number is expected to rise to about 22 % [20]. By 2050, 4 out of 5 people over 60 will live in developing countries [21]. In this population group, approximately 90 % of TB cases are due to reactivation of primary infection [22]. Ageing is associated with a decline in T cell proliferation and reduced synthesis of interferon gamma (IFN-γ), [23] which compromises body’s protective defenses against TB. In turn, by compounding the decrease in IFN – γ DM predisposes the ageing patient to infections where cell-mediated immunity plays a pivotal role, such as tuberculosis. Moreover, ageing and DM act synergistically and further aggravate protein-energy malnutrition (PEM), which is common in chronic disease states and is associated with increased morbidity and mortality [24]. This tripartite interaction additionally impairs T-lymphocyte
Page 2 of 11
mediated immunologic defenses, increasing the risk of certain infectious diseases [25]. According to the WHO, the number of people with TB attributable to PEM may exceed the number of people whose TB develops secondary to HIV infection, smoking or DM [26]. The negative impact of undernutrition on cell-mediated immunity is well documented [25, 27–29]. Malnutrition and infection interact with each other synergistically. Recurrent TB may cause loss of body nitrogen and worsened nutritional status. The resulting malnutrition may in turn increase the susceptibility to recurrent infection. Using data from existing literature, this article aims to highlight the synergistic mechanisms associated with immunosenescence and DM in relation to development of active TB. This includes the possible association between ageing and development of TB and/or PEM and the possible association between TB and PEM. The possibility of treatment for latent TB in the ageing population with DM is also explored. Finally, this paper aims to identify the clinical and epidemiological research gaps which need to be addressed in order to curb transmission.
Method To explore the synergistic relationship between ageing, DM, tuberculosis and PEM, the MEDLINE and the Google Scholar databases were searched for articles published from 1960 to March 2015. The following keywords were identified using medical subject headings and truncations: Synergistic biological mechanisms between DM, ageing TB population and PEM Ageing and TB
("ageing"[MeSH Terms] OR "ageing"[All Fields]) AND ("tuberculosis"[MeSH Terms] OR "tuberculosis"[All Fields]) yields 523 results Ageing and DM
("ageing"[MeSH Terms] OR "ageing"[All Fields]) AND ("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields]) yields 8131 results Ageing and PEM
("ageing"[MeSH Terms] OR "ageing"[All Fields]) AND ("protein-energy malnutrition"[MeSH Terms] OR ("protein-energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein-energy malnutrition"[All Fields] OR ("protein"[All Fields] AND "energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein energy malnutrition"[All Fields]) yields 363 results
Menon et al. BMC Infectious Diseases (2016) 16:361
PEM and TB
("protein-energy malnutrition"[MeSH Terms] OR ("protein-energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein-energy malnutrition"[All Fields] OR ("protein"[All Fields] AND "energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein energy malnutrition"[All Fields]) AND ("tuberculosis"[MeSH Terms] OR "tuberculosis"[All Fields] yields 91 results BMI and TB
BMI[All Fields] AND TB[All Fields] yields 2666 results. Treatment of latent TB in ageing population with DM
("therapy"[Subheading] OR "therapy"[All Fields] OR "treatment"[All Fields] OR "therapeutics"[MeSH Terms] OR "therapeutics"[All Fields]) AND ("latent tuberculosis"[MeSH Terms] OR ("latent"[All Fields] AND "tuberculosis"[All Fields]) OR "latent tuberculosis"[All Fields])) AND ("ageing"[MeSH Terms] OR "ageing"[All Fields])] yields 19 results Diabetes mellitus and multi drug resistant TB
("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields]) AND multi [All Fields] AND ("drug resistance"[MeSH Terms] OR ("drug"[All Fields] AND "resistance"[All Fields]) OR "drug resistance"[All Fields] OR ("drug"[All Fields] AND "resistant"[All Fields]) OR "drug resistant"[All Fields]) AND TB. [All Fields] yields 19 results Diabetes mellitus and multi-drug resistant TB treatment
("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields]) AND multi[All Fields] AND ("drug resistance"[MeSH Terms] OR ("drug"[All Fields] AND "resistance"[All Fields]) OR "drug resistance"[All Fields] OR ("drug"[All Fields] AND "resistant"[All Fields]) OR "drug resistant"[All Fields]) AND TB[All Fields] AND ("therapy"[Subheading] OR "therapy"[All Fields] OR "treatment"[All Fields] OR "therapeutics"[MeSH Terms] OR "therapeutics"[All Fields]) yields 15 results DM and PEM
"diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields]) AND ("protein-energy malnutrition"[MeSH Terms] OR ("protein-energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein-energy malnutrition"[All Fields] OR ("protein"[All Fields] AND "energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein energy malnutrition"[All Fields]) yields 164 Bibliographic search included WHO policy papers, personal communication, original articles and review
Page 3 of 11
articles written in English, French and Spanish. The following retrieved studies were included: longitudinal studies, randomized controlled trials, reviews or other comparative studies. Case reports were excluded. The included studies were then reviewed by two authors, and major findings reported. No ethical approval was required as this is a comprehensive paper without primary data collection.
Results Of the studies retrieved from the above-mentioned electronic database, 13 epidemiological studies and 6 (systematic reviews)/meta-analyses were included in this review. They are summarized in the Table 1 below: The studies included in this review revealed the following outcomes: Synergistic effects between TB, immunosenescence and DM
Immunosenescence and DM act synergistically to limit macrophage activation, which in turn decreases IL 12 and consequently IFN gamma, which is believed to play a central role in CMI against intracellular infection primarily by acting on Natural Killer (NK) and T cells. This is achieved through the following mechanisms: Mononuclear phagocytes
Activated mononuclear phagocytes stimulate granuloma formation in response to infection. As humans age, the macrophage capacity for phagocytosis diminishes, which is why the oxidative burst is compromised in elderly persons [30]. In a study involving TB patients, alveolar macrophages were less activated and had lower hydrogen peroxide production in those with DM comorbidity [31]. Additionally, in aged individuals the up-regulation of the major histocompatibility complex (MHC) class I and II expression as well as the antigen presentation capacity are reduced in dendritic cells, [32] which as a corollary diminishes interleukin 2 production and reduces T-cell proliferation. DM has been shown to hamper receptorbound material, [33] which further limits the role of antigen-presenting cells in lymphocyte activation by preventing the phagocytes from binding and internalizing the antigen, for processing and presentation via their Fc receptors. Natural Killer (NK) cells
It is well known that in elderly humans NK cells show diminished cytotoxic capacity on a 'per cell' basis [34]. Other aspects of NK cell function, such as the secretion of IFN-γ in response to IL-2 and IL 12 are also compromised in the aging population [35]. The decrease in IFN-γ produced by NK cells is further emphasized in individuals with concomitant DM.
Menon et al. BMC Infectious Diseases (2016) 16:361
Page 4 of 11
Table 1 Table summarizing the findings of the studies used in this review First author
Year of Study design and sample size publication
Main exposure(s) of interest
Main outcome(s) of interest
Main results and Remarks
Peleg AY
2007
Literature review
Glycaemic control
Risk of common community acquired infections
Further research is needed to improve understanding of the role of diabetes and glycaemic control in the pathogenesis and management of community and hospital acquired infections
Leung CC
2008
Cohort study 42,116 clients aged 65 years or more,
Diabetes mellitus
TB
Among diabetic subjects, higher risks of active, culture-confirmed, and pulmonary but not extrapulmonary tuberculosis were observed, with baseline hemoglobin A1c ≥7 % (vs.
REVIEW
Open Access
Convergence of a diabetes mellitus, protein energy malnutrition, and TB epidemic: the neglected elderly population Sonia Menon1,2*, Rodolfo Rossi3, Leon Nshimyumukiza4, Aibibula Wusiman5, Natasha Zdraveska6 and Manal Shams Eldin7
Abstract Background: On a global scale, nearly two billion persons are infected with Mycobacterium tuberculosis. From this vast reservoir of latent tuberculosis (TB) infection, a substantial number will develop active TB during their lifetime, with some being able to transmit TB or Multi-drug- resistant (MDR) TB to others. There is clinical evidence pointing to a higher prevalence of infectious diseases including TB among individuals with Diabetes Mellitus (DM). Furthermore, ageing and diabetes mellitus may further aggravate protein-energy malnutrition (PEM), which in turn impairs Tlymphocyte mediated immunologic defenses, thereby increasing the risk of developing active TB and compromising TB treatment. This article aims to a) highlight synergistic mechanisms associated with immunosenescence, DM and PEM in relation to the development of active TB and b) identify nutritional, clinical and epidemiological research gaps. Methods: To explore the synergistic relationship between ageing, DM, tuberculosis and PEM, a comprehensive review was undertaken. The MEDLINE and the Google Scholar databases were searched for articles published from 1990 to March 2015, using different MESH keywords in various combinations. Results: Ageing and DM act synergistically to reduce levels of interferon gamma (IFN- γ), thereby increasing susceptibility to TB, for which cell mediated immunity (CMI) plays an instrumental role. These processes can set in motion a vicious nutritional cycle which can predispose to PEM, further impairing the CMI and consequently limiting host defenses. This ultimately transforms the latent TB infection into active disease. A clinical diagnostic algorithm and clinical guidelines need to be established for this population. Conclusion: Given the increase in ageing population with DM and PEM, especially in resource-poor settings, these synergistic tripartite interactions must be examined if a burgeoning TB epidemic is to be averted. Implementation of a comprehensive, all-encompassing approach to curb transmission is clearly indicated. To this end, clinical, nutritional and epidemiological research gaps must be addressed without a delay.
Background TB infection occurs when a susceptible person inhales droplets containing Mycobacterium tuberculosis bacteria, which travel through the respiratory tract to the alveoli. In most patients, host’s immune response limits the propagation of TB infection, resulting in an asymptomatic, non-transmissible localized infection that may remain in the body for many years, if not forever. * Correspondence: [email protected] 1 International Centre for Reproductive health, Ghent University, LSHTM Alumni, Ghent, Belgium 2 CDC Foundation, Atlanta, USA Full list of author information is available at the end of the article
One in three people in the world has latent tuberculosis [1]. In 2009, approximately 9 million new cases of active TB were diagnosed and 1.7 million persons succumbed to the disease [2]. An additional challenge to TB control efforts is the global increase in multi-drug resistant TB (MDR-TB), defined as TB caused by strains resistant to at least isoniazid and rifampin. In 2013, the World Health Organization (WHO) reported that 3.6 % of the new cases and 20.2 % of the previously treated cases had MDR-TB [3]. Concurrently, diabetes mellitus (DM) is burgeoning as a worldwide chronic health condition, which can be attributed to increases in obesity, changing patterns of
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Menon et al. BMC Infectious Diseases (2016) 16:361
diet and physical activity as well as ageing [4, 5]. According to WHO estimates, there are currently 347 million people worldwide affected by DM, [6] and by 2030 its prevalence is projected to increase by 50 % [6]. 3/4 of diabetic patients live in low-income countries [7–9]. It is now well-established that cellular immune responses mediated by T cells and macrophages play a major role in the defense against TB [10]. In particular, the Th1 cytokine interferon (IFN)-γ is considered a principal mediator of protective immunity against TB [11, 12] DM is a clinical syndrome associated with deficiency of insulin secretion or resistance to its actions. Apart from the classical micro and macrovascular complications of the disease, DM has been associated with reduced T cell response and neutrophil functional activity as well as humoral immunity disorders, [13, 14] which in turn compromises the protective role that cellular immune response plays against TB. Consequently, DM patients show increased susceptibility to infections, notably TB, compared to individuals without DM [2, 15]. Some studies have shown that TB/DM comorbidity is common, both in low-income and high-income countries. [2, 16]. A 2008 systematic review of literature which identified 13 age-adjusted, quantitative, observational studies in North America, UK, Russia, Mexico, Korea, Taiwan and India reported a relative risk of TB in DM patients of 3.1 in cohort studies, with odds ratios ranging from 1.16 to 7.83 in case control studies [17]. An epidemiological model indicated that in India DM might account for nearly 15 % of pulmonary tuberculosis (PTB) cases [18]. In diabetic patients, pulmonary TB may progress rapidly and hence requires a high index of suspicion in the diagnostic phase [19]. Furthermore, the rising number of ageing diabetic population at risk for TB represents a worldwide health threat. People aged 60 and older make up over 11 % of the global population and by 2050 that number is expected to rise to about 22 % [20]. By 2050, 4 out of 5 people over 60 will live in developing countries [21]. In this population group, approximately 90 % of TB cases are due to reactivation of primary infection [22]. Ageing is associated with a decline in T cell proliferation and reduced synthesis of interferon gamma (IFN-γ), [23] which compromises body’s protective defenses against TB. In turn, by compounding the decrease in IFN – γ DM predisposes the ageing patient to infections where cell-mediated immunity plays a pivotal role, such as tuberculosis. Moreover, ageing and DM act synergistically and further aggravate protein-energy malnutrition (PEM), which is common in chronic disease states and is associated with increased morbidity and mortality [24]. This tripartite interaction additionally impairs T-lymphocyte
Page 2 of 11
mediated immunologic defenses, increasing the risk of certain infectious diseases [25]. According to the WHO, the number of people with TB attributable to PEM may exceed the number of people whose TB develops secondary to HIV infection, smoking or DM [26]. The negative impact of undernutrition on cell-mediated immunity is well documented [25, 27–29]. Malnutrition and infection interact with each other synergistically. Recurrent TB may cause loss of body nitrogen and worsened nutritional status. The resulting malnutrition may in turn increase the susceptibility to recurrent infection. Using data from existing literature, this article aims to highlight the synergistic mechanisms associated with immunosenescence and DM in relation to development of active TB. This includes the possible association between ageing and development of TB and/or PEM and the possible association between TB and PEM. The possibility of treatment for latent TB in the ageing population with DM is also explored. Finally, this paper aims to identify the clinical and epidemiological research gaps which need to be addressed in order to curb transmission.
Method To explore the synergistic relationship between ageing, DM, tuberculosis and PEM, the MEDLINE and the Google Scholar databases were searched for articles published from 1960 to March 2015. The following keywords were identified using medical subject headings and truncations: Synergistic biological mechanisms between DM, ageing TB population and PEM Ageing and TB
("ageing"[MeSH Terms] OR "ageing"[All Fields]) AND ("tuberculosis"[MeSH Terms] OR "tuberculosis"[All Fields]) yields 523 results Ageing and DM
("ageing"[MeSH Terms] OR "ageing"[All Fields]) AND ("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields]) yields 8131 results Ageing and PEM
("ageing"[MeSH Terms] OR "ageing"[All Fields]) AND ("protein-energy malnutrition"[MeSH Terms] OR ("protein-energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein-energy malnutrition"[All Fields] OR ("protein"[All Fields] AND "energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein energy malnutrition"[All Fields]) yields 363 results
Menon et al. BMC Infectious Diseases (2016) 16:361
PEM and TB
("protein-energy malnutrition"[MeSH Terms] OR ("protein-energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein-energy malnutrition"[All Fields] OR ("protein"[All Fields] AND "energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein energy malnutrition"[All Fields]) AND ("tuberculosis"[MeSH Terms] OR "tuberculosis"[All Fields] yields 91 results BMI and TB
BMI[All Fields] AND TB[All Fields] yields 2666 results. Treatment of latent TB in ageing population with DM
("therapy"[Subheading] OR "therapy"[All Fields] OR "treatment"[All Fields] OR "therapeutics"[MeSH Terms] OR "therapeutics"[All Fields]) AND ("latent tuberculosis"[MeSH Terms] OR ("latent"[All Fields] AND "tuberculosis"[All Fields]) OR "latent tuberculosis"[All Fields])) AND ("ageing"[MeSH Terms] OR "ageing"[All Fields])] yields 19 results Diabetes mellitus and multi drug resistant TB
("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields]) AND multi [All Fields] AND ("drug resistance"[MeSH Terms] OR ("drug"[All Fields] AND "resistance"[All Fields]) OR "drug resistance"[All Fields] OR ("drug"[All Fields] AND "resistant"[All Fields]) OR "drug resistant"[All Fields]) AND TB. [All Fields] yields 19 results Diabetes mellitus and multi-drug resistant TB treatment
("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields]) AND multi[All Fields] AND ("drug resistance"[MeSH Terms] OR ("drug"[All Fields] AND "resistance"[All Fields]) OR "drug resistance"[All Fields] OR ("drug"[All Fields] AND "resistant"[All Fields]) OR "drug resistant"[All Fields]) AND TB[All Fields] AND ("therapy"[Subheading] OR "therapy"[All Fields] OR "treatment"[All Fields] OR "therapeutics"[MeSH Terms] OR "therapeutics"[All Fields]) yields 15 results DM and PEM
"diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields]) AND ("protein-energy malnutrition"[MeSH Terms] OR ("protein-energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein-energy malnutrition"[All Fields] OR ("protein"[All Fields] AND "energy"[All Fields] AND "malnutrition"[All Fields]) OR "protein energy malnutrition"[All Fields]) yields 164 Bibliographic search included WHO policy papers, personal communication, original articles and review
Page 3 of 11
articles written in English, French and Spanish. The following retrieved studies were included: longitudinal studies, randomized controlled trials, reviews or other comparative studies. Case reports were excluded. The included studies were then reviewed by two authors, and major findings reported. No ethical approval was required as this is a comprehensive paper without primary data collection.
Results Of the studies retrieved from the above-mentioned electronic database, 13 epidemiological studies and 6 (systematic reviews)/meta-analyses were included in this review. They are summarized in the Table 1 below: The studies included in this review revealed the following outcomes: Synergistic effects between TB, immunosenescence and DM
Immunosenescence and DM act synergistically to limit macrophage activation, which in turn decreases IL 12 and consequently IFN gamma, which is believed to play a central role in CMI against intracellular infection primarily by acting on Natural Killer (NK) and T cells. This is achieved through the following mechanisms: Mononuclear phagocytes
Activated mononuclear phagocytes stimulate granuloma formation in response to infection. As humans age, the macrophage capacity for phagocytosis diminishes, which is why the oxidative burst is compromised in elderly persons [30]. In a study involving TB patients, alveolar macrophages were less activated and had lower hydrogen peroxide production in those with DM comorbidity [31]. Additionally, in aged individuals the up-regulation of the major histocompatibility complex (MHC) class I and II expression as well as the antigen presentation capacity are reduced in dendritic cells, [32] which as a corollary diminishes interleukin 2 production and reduces T-cell proliferation. DM has been shown to hamper receptorbound material, [33] which further limits the role of antigen-presenting cells in lymphocyte activation by preventing the phagocytes from binding and internalizing the antigen, for processing and presentation via their Fc receptors. Natural Killer (NK) cells
It is well known that in elderly humans NK cells show diminished cytotoxic capacity on a 'per cell' basis [34]. Other aspects of NK cell function, such as the secretion of IFN-γ in response to IL-2 and IL 12 are also compromised in the aging population [35]. The decrease in IFN-γ produced by NK cells is further emphasized in individuals with concomitant DM.
Menon et al. BMC Infectious Diseases (2016) 16:361
Page 4 of 11
Table 1 Table summarizing the findings of the studies used in this review First author
Year of Study design and sample size publication
Main exposure(s) of interest
Main outcome(s) of interest
Main results and Remarks
Peleg AY
2007
Literature review
Glycaemic control
Risk of common community acquired infections
Further research is needed to improve understanding of the role of diabetes and glycaemic control in the pathogenesis and management of community and hospital acquired infections
Leung CC
2008
Cohort study 42,116 clients aged 65 years or more,
Diabetes mellitus
TB
Among diabetic subjects, higher risks of active, culture-confirmed, and pulmonary but not extrapulmonary tuberculosis were observed, with baseline hemoglobin A1c ≥7 % (vs.
